10-102504168-C-T

Position:

• chr10-102504168-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_016169.4(SUFU):​c.16C>T​(p.Pro6Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000287 in 1,393,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.93

Genes affected

SUFU (HGNC:16466): (SUFU negative regulator of hedgehog signaling) The Hedgehog signaling pathway plays an important role in early human development. The pathway is a signaling cascade that plays a role in pattern formation and cellular proliferation during development. This gene encodes a negative regulator of the hedgehog signaling pathway. Defects in this gene are a cause of medulloblastoma. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SUFU. . Gene score misZ 1.9341 (greater than the threshold 3.09). Trascript score misZ 3.1202 (greater than threshold 3.09). GenCC has associacion of gene with apraxia, ciliopathy, ocular motor apraxia, Cogan type, nevoid basal cell carcinoma syndrome, Joubert syndrome, Joubert syndrome 32, medulloblastoma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23800656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUFU	NM_016169.4	c.16C>T	p.Pro6Ser	missense_variant	1/12	ENST00000369902.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUFU	ENST00000369902.8	c.16C>T	p.Pro6Ser	missense_variant	1/12	1	NM_016169.4	P1
SUFU	ENST00000423559.2	c.16C>T	p.Pro6Ser	missense_variant	1/10	1
SUFU	ENST00000369899.6	c.16C>T	p.Pro6Ser	missense_variant	1/11	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1393806 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 687576

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000371

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 6 of the SUFU protein (p.Pro6Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SUFU-related conditions. ClinVar contains an entry for this variant (Variation ID: 1024959). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. -

Familial meningioma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 26, 2023

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2022

The p.P6S variant (also known as c.16C>T), located in coding exon 1 of the SUFU gene, results from a C to T substitution at nucleotide position 16. The proline at codon 6 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.1	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.88	N;N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.41	T;T;T
Polyphen		0.27	B;B;P
Vest4		0.31
MutPred		0.14		Gain of phosphorylation at P6 (P = 0.0137);Gain of phosphorylation at P6 (P = 0.0137);Gain of phosphorylation at P6 (P = 0.0137);
MVP		0.34
MPC		1.2
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.85
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2062288467; hg19: chr10-104263925;